Advancing selective pyrazinyl aminothiazole derivatives for the treatment of primary liver cancer

ABSTRACT Hepatocellular carcinomaHCCis fastest or second fastest growing cancerin incidencein the USwith more thancases this yearaloneIt is consistently one of the deadliestwithyear survivalseven with treatmentoften of less thanAlthough liver transplant can be usefulif done earlythere are fewif anymedical options that result in meaningful beneficial outcomesNew therapeutics are desperately neededThis is a Phase I feasibility study to determine if the pharmacological properties of a small moleculewith striking activity against hepatocellular carcinomaHCCcells in vitroin vivo and in ex vivo modelscan be improved by straightforward medicinal chemistry approachesBrieflySQand itsrd generation progenySQare aminothiazoles with potent anti HCC activity in tissue cultureCCs of less thannM for HCCand selectivity indexes with non cancerous liver cells of greater thanthat appear to work via inhibition of the mTOR pathwayThe promising activityis not only in tissue culturebut in xenograft models in miceand perhaps most compellingagainst human liver tumors in explantex vivomodelsHoweveralthough theySQhave high selectivity and low toxicitythey exhibit metabolic instability and other pharmacokineticPKlimitationsFor exampleSQis rapidly metabolizedand two major metabolites are identified as an ester hydrolyzed acid and oxidized amino pyrimidinewhich are likely a significant contributor to its poor PK performanceIn this studywe will employ several strategies to further optimize this lead structure to discover the hydrolysis resistant ester replacements and inoxidizable amino pyrimidine bioisosteresThe new SQderivatives will be tested for better metabolic stability and PK and assuring the observed selectivity and low toxicity is maintained or improvedAt the end of the proposed projectmore metabolically stable and more bioavailable new leads will be delivered ready for the next stage of preclinical studiesHCC liver cancer is theth leading cause of cancer World Wide with onlyapproved drugs for treatment that provides medianmonths progression free survival with andltresponse rateVarious compounds are currently under study that rely on similar mechanismsSQderived analogs that we propose to develop will have more drug like potential and novel selective effect to cancerous liver cells but not normal liver cells